Several kinds of bis-dioxopiperazine derivatives have been already reported. Among them, especially known as compounds having antitumor activity are 1,2-bis(4-morpholinomethyl-3,5-dioxopiperazin-1-yl)ethane (see Abstract, 8th International Congress of Pharmacology p441, 1981), d1-1,2-bis(4-morpholinomethyl-3,5-dioxopiperazin-1-yl)propane (see Japanese Patent Publication (Kokai) No. 190976/1984) and 1,2-bis(4-isobutoxycarbonyloxymethyl-3,5-dioxopiperazin-1-yl)ethane (see Abstract, 14th International Congress of Chemotherapy p324, 1985 and Japanese Patent Publication (Kokai) No. 97963/1985). Also known are the compounds described in the Japanese Patent Publication (Kokai) Nos. 152660/1986, 89668/1987, 281870/1987 and 279875/1989.
Though these compounds have excellent antitumor activity, water soluble salts thereof with retained activity cannot be formed so that route of administration and pharmaceutical form of the compounds are much limitative. Therefore, there has been a demand for a water soluble bis-dioxopiperazine derivative which may be expected to have wider clinical applicabilities.
Under these circumstances, we, the inventors carried out studies on novel bis-dioxopiperazine derivatives to find out that acid addition salts of the compounds represented by the formula (I) exhibit remarkably excellent antitumor activity, thus completing the present invention.
The terms used for definition of variables in the above-mentioned formulas (I) and (II) by which the compound of the present invention and synthetic intermediates thereof are respectively represented are defined and exemplified in the following.
The "C.sub.1-6 " refers to a group having 1 to 6 carbon atoms unless otherwise indicated.
The "C.sub.1-6 alkyl group" refers to a straight- or branched-chain alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl or the like. Preferably, methyl is used for R.sup.1.
The "C.sub.1-6 alkoxy group" refers to a straight-or branched-chain alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, n-hexyloxy or the like.
The "protective group for amino group" may be tert-butoxycarbonyl, benzyloxycarbonyl or the like.
The compound of the present invention are for example as follows:
2,3-bis[4-(2-aminoacetoxymethyl)-3,5-dioxopiperazin-1-yl]butane PA0 2,3-bis[4-(2-aminopropionyloxymethyl)-3,5-dioxopiperazin-1-yl]butane PA0 2,3-bis[4-(2-aminoisovaleryloxymethyl)-3,5-dioxopiperazin-1-yl]butane PA0 2,3-bis[4-(2-amino-4-methylvaleryloxymethyl)-3,5-dioxopiperazin-1-yl]butane PA0 2,3-bis[4-(2-amino-3,3-dimethylbutyryloxymethyl)-3,5-dioxopiperazin-1-yl]bu tane PA0 2,3-bis[4-(2-amino-4,4-dimethylvaleryloxymethyl)-3,5-dioxopiperazin-1-yl]bu tane PA0 2,3-bis[4-(2-amino-3-phenylpropionyloxymethyl)-3,5-dioxopiperazin-1-yl]buta ne PA0 2,3-bis[4-(2-amino-6-phenylhexanoyloxymethyl)-3,5-dioxopiperazin-1-yl]-buta ne PA0 2,3-bis[4-(2-amino-3-(p-trifluoromethylphenyl)propionyloxymethyl)-3,5-dioxo piperazin-1-yl]butane PA0 2,3-bis[4-(2-amino-3-(p-hydroxyphenyl)propionyloxymethyl)-3,5-dioxopiperazi n-1-yl]butane PA0 2,3-bis[4-(2-amino-3-(p-benzyloxyphenyl)propionyloxymethyl)-3,5-dioxopipera zin-1-yl]butane PA0 2,3-bis[4-(3-(p-acetoxyphenyl)-2-aminopropionyloxymethyl)-3,5-dioxopiperazi n-1-yl]butane PA0 2,3-bis[4-(2-amino-3-carboxypropionyloxymethyl)-3,5-dioxopiperazin- 1-yl]butane PA0 2,3-bis[4-(2-amino-4-carboxybutyryloxymethyl)-3,5-dioxopiperazin-1-yl]butan e PA0 2,3-bis[4-(2-amino-3-benzyloxycarbonylpropionyloxymethyl)-3,5-dioxopiperazi n-1-yl]butane PA0 2,3-bis[4-(2-amino-4-benzyloxycarbonylbutyryloxymethyl)-3,5-dioxopiperazin- 1-yl]butane PA0 2,3-bis[4-(2,4-diaminobutyryloxymethyl)-3,5-dioxopiperazin-1-yl]butane PA0 2,3-bis[4-(2,6-diaminohexanoyloxymethyl)-3,5-dioxopiperazin-1-yl]butane PA0 2,3-bis[4-(2-amino-3-mercaptopropionyloxymethyl)-3,5-dioxopiperazin-1-yl]bu tane PA0 2,3-bis(4-pyrrolidinecarbonyloxymethyl-3,5-dioxopiperazin-1-yl)butane PA0 2,3-bis(4-thiazolydinecarbonyloxymethyl-3,5-dioxopiperazin-1-yl)butane PA0 2-[4-(2-aminoacetoxymethyl)-3,5-dioxopiperazin-1-yl]-3-(3,5-dioxopiperazin- 1-yl)butane PA0 2-[4-(2-aminopropionyloxymethyl)-3,5-dioxopiperazin-1-yl]-3-(3,5-dioxopiper azin-1-yl)butane PA0 2-[4-(2-aminobutyryloxymethyl)-3,5-dioxopiperazin-1-yl]-3-(3,5-dioxopiperaz in-1-yl)butane PA0 2-[4-(2-aminovaleryloxymethyl)-3,5-dioxopiperazin-1-yl]-3-(3,5-dioxopiperaz in-1-yl)butane PA0 2-[4-(2-amino-4-methylvaleryloxymethyl)-3,5-dioxopiperazin-1-yl]-3-(3,5-dio xopiperazin-1-yl)butane PA0 2-[4-(2-amino-3-(p-hydroxyphenyl)propionyloxymethyl)-3,5-dioxopiperazin-1-y l]-3-(3,5-dioxopiperazin-1-yl)butane PA0 2-[4-(2-amino-3-carboxypropionyloxymethyl)-3,5-dioxopiperazin-1-yl]-3-(3,5- dioxopiperazin-1-yl)butane PA0 2-[4-(2-amino-6-N-benzyloxycarbonylaminohexanoyloxymethyl)-3,5-dioxopiperaz in-1-yl]-3-(3,5-dioxopiperazin-1-yl)butane PA0 2-(4-pyrrolidinecarbonyloxymethyl-3,5-dioxopiperazin-1-yl)-3-(3,5-dioxopipe razin-1-yl)butane PA0 2-(4-thiazolidinecarbonyloxymethyl-3,5-dioxopiperazin-1-yl)-3-(3,5-dioxopip erazin-1-yl)butane PA0 2,3-bis[4-(2-N-tert-butoxycarbonylaminoacetoxymethyl)-3,5-dioxopiperazin-1- yl]butane PA0 2,3-bis[4-(2-N-tert-butoxycarbonylaminopropionyloxymethyl)-3,5-dioxopiperaz in-1-yl]butane PA0 2,3-bis[4-(2-N-tert-butoxycarbonylaminoisovaleryloxymethyl)-3,5-dioxopipera zin-1-yl]butane PA0 2,3-bis[4-(2-N-benzyloxycarbonylamino-4-methylvaleryloxymethyl)-3,5-dioxopi perazin-1-yl]butane PA0 2,3-bis[4-(2-N-benzyloxycarbonylamino-3,3-dimethylbutyryloxymethyl)-3,5-dio xopiperazin-1-yl]butane PA0 2,3-bis[4-(2-N-benzyloxycarbonylamino-4,4-dimethylvaleryloxymethyl)- 3,5-dioxopiperazin-1-yl]butane PA0 2,3-bis[4-(2-N-tert-butoxycarbonylamino-3-phenylpropionyloxymethyl)-3,5-dio xopiperazin-1-yl]butane PA0 2,3-bis[4-(2-N-tert-butoxycarbonylamino-6-phenylhexanoyloxymethyl)-3,5-diox opiperazin-1-yl]butane PA0 2,3-bis[4-(2-N-tert-butoxycarbonylamino-3-(p-trifluoromethylphenyl)propiony loxymethyl)-3,5-dioxopiperazin-1-yl]butane PA0 2,3-bis[4-(2-N-tert-butoxycarbonylamino-3-(p-hydroxyphenyl)propionyloxymeth yl)-3,5-dioxopiperazin-1-yl]butane PA0 2,3-bis[4-(3-(p-benzyloxyphenyl)-2-N-tert-butoxycarbonylaminopropionyloxyme thyl)-3,5-dioxopiperazin-1-yl]butane PA0 2,3-bis[4-(3-(p-acetoxyphenyl)-2-N-tert-butoxycarbonylaminopropionyloxymeth yl)-3,5-dioxopiperazin-1-yl]butane PA0 2,3-bis[4-(2-N-tert-butoxycarbonylamino-3-carboxypropionyloxymethyl)-3,5-di oxopiperazin-1-yl]butane PA0 2,3-bis[4-(2-N-tert-butoxycarbonylamino-4-carboxybutyryloxymethyl)-3,5-diox opiperazin-1-yl]butane PA0 2,3-bis[4-(3-benzyloxycarbonyl-2-N-tert-butoxycarbonylaminopropionyloxymeth yl)-3,5-dioxopiperazin-1-yl]butane PA0 2,3-bis[4-(4-benzyloxycarbonyl-2-N-tert-butoxycarbonylaminobutyryloxymethyl )-3,5-dioxopiperazin-1-yl]butane PA0 2,3-bis[4-(6-N-benzyloxycarbonylamino-2-N-tert-butoxycarbonylaminohexanoylo xymethyl)-3,5-dioxopiperazin-1-yl]butane PA0 2,3-bis[4-(4-N-benzyloxycarbonylamino-2-N-tert-butoxycarbonylaminobutyrylox ymethyl)-3,5-dioxopiperazin-1-yl]butane PA0 2,3-bis[4-(2-N-tert-butoxycarbonylamino-3-(p-methoxybenzylthio)propionyloxy methyl-3,5-dioxopiperazin-1-yl]butane PA0 2,3-bis(4-N-tert-butoxycarbonylpyrrolidinecarbonyloxymethyl-3,5-dioxopipera zin-1-yl)butane PA0 2,3-bis(4-N-tert-butoxycarbonylthiazolidinecarbonyloxymethyl-3,5-dioxopiper azin-1-yl)butane PA0 2-[4-(2-N-tert-butoxycarbonylaminoacetoxymethyl)-3,5-dioxopiperazin-1-yl]-3 -(3,5-dioxopiperazin-1-yl)butane PA0 2-[4-(2-N-tert-butoxycarbonylaminopropionyloxymethyl)-3,5-dioxopiperazin-1- yl]-3-(3,5-dioxopiperazin-1-yl)butane PA0 2-[4-(2-N-tert-butoxycarbonylaminobutyryloxymethyl)-3,5-dioxopiperazin-1-yl ]-3-(3,5-dioxopiperazin-1-yl)butane PA0 2-[4-(2-N-tert-butoxycarbonylaminovaleryloxymethyl)-3,5-dioxopiperazin-1-yl ]-3-(3,5-dioxopiperazin-1-yl)butane PA0 2-[4-(2-N-benzyloxycarbonylamino-4-methylvaleryloxymethyl)-3,5-dioxopiperaz in-1-yl]-3-(3,5-dioxopiperazin-1-yl)butane PA0 2-[4-(3-(p-benzyloxyphenyl)-2-N-tert-butoxycarbonylaminopropionyloxymethyl) -3,5-dioxopiperazin-1-yl]-3-(3,5-dioxopiperazin-1-yl)butane PA0 2-[4-(3-benzyloxycarbonyl-2-N-tert-butoxycarbonylaminopropionyloxymethyl)-3 ,5-dioxopiperazin-1-yl]-3-(3,5-dioxopiperazin-1-yl)butane PA0 2-[4-(2-N-tert-butoxycarbonylamino-3-carboxypropionyloxymethyl)-3,5-dioxopi perazin-1-yl]-3-(3,5-dioxopiperazin-1-yl)butane PA0 2-[4-(6-N-benzyloxycarbonylamino-2-N-tert-butoxycarbonylaminohexanoyloxymet hyl)-3,5-dioxopiperazin-1-yl]-3-(3,5-dioxopiperazin-1-yl)butane PA0 2-(4-N-tert-butoxycarbonylpyrrolidinecarbonyloxymethyl-3,5-dioxopiperazin-1 -yl)-3-(3,5-dioxopiperazin-1-yl)butane PA0 2-(4-N-tert-butoxycarbonylthiazolidinecarbonyloxymethyl-3,5-dioxopiperazin- 1-yl)-3-(3,5-dioxopiperazin-1-yl)butane PA0 Sample 1: Meso-2,3-bis[4-(2-aminoacetoxymethyl)-3,5-dioxopiperazin-1-yl]butane.hydro chloride PA0 Sample 2: Meso-2,3-bis[4-((S)-2-aminopropionyloxymethyl)-3,5-dioxopiperazin-1-yl]but ane.hydrochloride PA0 Sample 3: Meso-2,3-bis[4-((S)-2-aminoisovaleryloxymethyl)-3,5-dioxopiperazin-1-yl]bu tane.hydrochloride PA0 Sample 4: Meso-2,3-bis[4-((S)-2-amino-4-methylvaleryloxymethyl)-3,5-dioxopiperazin-1 -yl]butane.hydrochloride PA0 Sample 5: Meso-2,3-bis[4-((S)-2-amino-3-phenylpropionyloxymethyl)-3,5-dioxopiperazin -1-yl]butane.hydrochloride PA0 Sample 6: Meso-2,3-bis[4-((S)-2-amino-3-(p-trifluoromethylphenyl)propionyloxymethyl) -3,5-dioxopiperazin-1-yl]butane.hydrochloride PA0 Sample 7: Meso-2,3-bis[4-((S)-2-amino-3-(p-hydroxyphenyl)propionyloxymethyl)-3,5-dio xopiperazin-1-yl]butane.hydrochloride PA0 Sample 8: Meso-2,3-bis[4-((S)-2-amino-3-(p-benzyloxyphenyl)propionyloxymethyl)-3,5-d ioxopiperazin-1-yl]butane.hydrochloride PA0 Sample 9: Meso-2,3-bis[4-((S)-3-(p-acetoxyphenyl)-2-aminopropionyloxymethyl)-3,5-dio xopiperazin-1-yl]butane.hydrochloride PA0 Sample 10: Meso-2,3-bis[4-((S)-2-amino-4-carboxybutyryloxymethyl)-3,5-dioxopiperazin- 1-yl]butane.hydrochloride PA0 Sample 11: Meso-2,3-bis[4-((S)-2-amino-4-benzyloxycarbonylbutyryloxymethyl)-3,5-dioxo piperazin-1-yl]butane.hydrochloride PA0 Sample 12: Meso-2,3-bis[4-((S)-2,6-diaminohexanoyloxymethyl)-3,5-dioxopiperazin-1-yl] butane.hydrobromide PA0 Sample 13: Meso-2,3-bis[4-((S)-2-amino-3-mercaptopropionyloxymethyl)-3,5-dioxopiperaz in-1-yl]butane.trifluoroacetate PA0 Sample 14: Meso-2,3-bis[4-(2-pyrrolidinecarbonyloxymethyl)-3,5-dioxopiperazin-1-yl]bu tane.hydrochloride PA0 Sample 15: Meso-2,3-bis[4-(4-thiazolidinecarbonyloxymethyl)-3,5-dioxopiperazin-1-yl]b utane.hydrochloride PA0 Sample 16: Erythro-2-[4-(2-aminoacetoxymethyl)-3,5-dioxopiperazin-1-yl]-3-(3,5-dioxop iperazin-1-yl)butane.trifluoroacetate PA0 Sample 17: Erythro-2-[4-((S)-2-aminopropionyloxymethyl)-3,5-dioxopiperazin-1-yl]-3-(3 ,5-dioxopiperazin-1-yl)butane.hydrochloride PA0 Sample 18: Erythro-2-[4-((S)-2-amino-4-methylvaleryloxymethyl)-3,5-dioxopiperazin-1-y l]-3-(3,5-dioxopiperazin-1-yl)butane.hydrochloride PA0 Sample 19: Erythro-2-[4-((S)-2-amino-3-(p-hydroxyphenyl)propionyloxymethyl)-3,5-dioxo piperazin-1-yl]-3-(3,5-dioxopiperazin-1-yl)butane.hydrochloride PA0 Sample 20: Erythro-2-[4-((S)-2-amino-3-carboxypropionyloxymethyl)-3,5-dioxopiperazin- 1-yl]-3-(3,5-dioxopiperazin-1-yl)butane.hydrochloride PA0 Sample 21: Erythro-2-[4-((S)-2-amino-6-benzyloxycarbonylaminohexanoyloxymethyl)-3,5-d ioxopiperazin-1-yl]-3-(3,5-dioxopiperazin-1-yl)butane.trifluoroacetate PA0 Sample A: 1,2-bis(4-isobutoxycarbonyloxymethyl-3,5-dioxopiperazin-1-yl)ethane PA0 Sample B: 1,2-bis[4-((R)-2-amino-2-phenylacetoxymethyl)-3,5-dioxopiperazin-1-yl]etha ne.trifluoroacetate (Typical water soluble compound disclosed in Japanese Patent Publication (Kokai) No. 152660/1986)
The compound (I) of the present invention has asymmetric carbon atoms in its molecules. It is to be understood that isomers due to such asymmetric carbon atom or combination of any of the isomers are included in the category of the compound (I). Especially, meso- or erythro-form is preferred.
Preferably, salts of the compounds of the present invention may be pharmaceutically acceptable salts such as hydrochloride, hydrobromide or trifluoroacetate.
A synthetic intermediate (II) of the present invention is a compound with a protecting group of an amino group which bonds R.sup.4 of the compound (I) and is for example as follows:
The compounds (I) of the present invention may be prepared by the reaction of compound represented by the formula (III): ##STR10## wherein R.sup.1 is as defined above, with a compound represented by the forumula (IV): ##STR11## wherein R.sup.6, R.sup.7 and R.sup.8 are as defined above, (A) in the presence of a condensing agent to thereby readily afford the synthetic intermediate (II), followed by (B) removal of the protecting group R.sup.8 of amino group by acidic hydrolysis or by catalytic reduction in the presence of an acid to thereby prepare the compound of the formula (I) or acid addition salt thereof.
In the reaction (A), the condensing agent may be, for example, 1-methyl-2-chloropyridinium iodide, dicyclohexylcarbodiimide or N,N'-carbonyldiimidazole. Preferably, methyl iodide is used as reaction accelerator in the case of N,N'-carbonyldiimidazole being a condensing agent used; and N,N-dimethylaminopyridine, in the case of the other condensing agents.
The reaction temperature may range from 0.degree. to 30.degree. C., and the reaction time may range from 16 to 48 hours depending on reaction temperature. In the above-mentioned reaction, 1.2 to 2.4 molar amount of the compound of the formula (IV) is used to one molar amount of the compound of the formula (III). As for the reaction solvent, an aprotic polar solvent such as N,N-dimethylformamide (DMF), pyridine, dichloromethane, chloroform, acetonitrile or their mixture may be used. In the above-mentioned reaction, the synthetic intermediates of the formula (II) with R.sup.5 being hydrogen atom and the group of ##STR12## are concurrently generated, and are separated and purified according to ordinary method using silica gel column chromatography or the like.
Moreover, when the synthetic intermediates (II) contain a protective group or groups for phenolic hydroxyl, carboxyl, amino or mercapto group in addition to the protective group R.sup.8, such protective group or groups can be removed together with the protective group R.sup.8 by the reaction (B).
When the acidic hydrolysis is used in the reaction (B), the acid may be for example hydrogen chloride, hydrogen bromide or trifluoroacetic acid. The amount of the acid between 20 and 30 moles is used to one molar amount of the synthetic intermediate (II). The reaction temperature may range from 0.degree. to 70.degree. C. and the reaction time may range from 2 to 4 hours depending on reaction temperature. As for the reaction solvent, dioxane, acetic acid or the like may be used.
In the catalytic reduction, 10% palladium on carbon, 5% palladium on barium sulfate, platinum oxide or the like may be used as a catalyst; 10% palladium on carbon or platinum oxide is preferable. The acid used may be, for example, acetic or hydrochloric acid; and the reaction solvent may be methanol, ethanol, acetic acid, dioxane or the like. The reaction temperature may range from 0.degree. to 70.degree. C. and the reaction time may range from 1 to 24 hours depending on reaction temperature.
Thus obtained compound of the present invention or acid addition salt thereof may be isolated by usual manners such as extraction, concentration, filtration or recrystallization.
The compound of the formula (III) which is the starting material in the above-mentioned preparation can be readily obtained from the reaction of bis(3,5-dioxopiperazin-1-yl)alkane, which disclosed in British Patent No. 1234935, with formaldehyde.
The antitumor activity of the compounds of the formula (I) according to the present invention and prepared by the above-mentioned preparation process was verified by the below-mentioned tests.
Test samples in these tests were as follows: